Abstract 4090: Regional administration of IL-12 endowed CAR T cells effectively targets systemic disease
Authors: Hee Jun Lee, Yuki Yamaguchi, Jackson Gibson, Cody Cullen, John P. Murad, Anthony K. Park, Isabel Monroy, Cari Young, Lea Christian, Lauren Adkins, Lawrence Stern, Wen-Chung Chang, Catalina Martinez, Stephen J. Forman, Saul J. Priceman
Journal: Cancer Research (2023)

Abstract While chimeric antigen receptor (CAR) T cells have received FDA approvals in treating hematological malignancies, clinical responses of CAR T cells for solid tumors have been underwhelming. Intense investigation is underway to improve CAR T cells trafficking, persistence and efficacy. Interleukin-12 (IL-12) is a potent inflammatory cytokine that recruits and activates various endogenous and adoptively transferred immune cells, but development of its clinical applications is hindered by toxicity of systemic IL-12 signaling. In this study, we engineered and expressed membrane-bound IL-12 (mbIL12) in CAR T cells to overcome current limitations in CAR T cell and IL-12 therapies. We evaluated CAR T cell function using co-culture assays and preclinical murine models bearing human tumor xenografts. We modeled systemic metastasis of ovarian and breast cancer and assessed the impact of mbIL12 in CAR T cells on targeting regional and systemic diseases. Syngeneic mouse models were used to evaluate toxicity induced by mbIL12 in CAR T cells. We observed a greater number of CAR T cells in the peripheral blood of mice receiving locoregionally delivered CAR T cells engineered with mbIL12, suggesting that mbIL12 improves CAR T cell trafficking and persistence. Furthermore, mice bearing regional and systemic diseases experienced more potent and durable anti-tumor activity when treated with mbIL12 endowed CAR T cells. These results were mirrored in vitro where mbIL12 improved CAR T cells activation, proliferation and IFNg secretion when co-cultured with tumor cells, recapitulating our findings in vivo. Toxicities observed in immune-competent mice receiving systemic IL-12 delivery were not detected in those administered CAR T cells with mbIL12. We demonstrated that mbIL12 enhances anti-tumor function of CAR T cells for treatment of solid tumors. This study also showed that mbIL12 is safe, providing a translatable engineering strategy to improve CAR T cell therapy. IL-12 signaling is well known to modulate function of various immune cells, but the impact of CAR T cells with mbIL12 on immune tumor microenvironments remains to be elucidated. We are currently investigating changes in the immune landscape that CAR T cells with mbIL12 induce. Citation Format: Hee Jun Lee, Yuki Yamaguchi, Jackson Gibson, Cody Cullen, John P. Murad, Anthony K. Park, Isabel Monroy, Cari Young, Lea Christian, Lauren Adkins, Lawrence Stern, Wen-Chung Chang, Catalina Martinez, Stephen J. Forman, Saul J. Priceman. Regional administration of IL-12 endowed CAR T cells effectively targets systemic disease. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4090.